The pharmaceutical industry has been developing compositions that include biologic therapeutic agents (e.g., biologics such as monoclonal antibodies) for many years for the treatment of a variety of maladies. Such biologics tend to be relatively large molecules which are quite amenable to oral delivery and some forms of parenteral delivery. However, biologics can present drawbacks for delivery by injection, particularly intravitreal injection. Due to their size, biologics, when included in aqueous compositions, often impart substantial viscosity to those compositions. In turn, such compositions can be difficult to administer through an injection device (e.g., a syringe). However, injection of a biologic at a site of a disease or malady is quite desirable.
As a consequence, the pharmaceutical industry has committed substantial resources to developing techniques to lower the viscosity of aqueous compositions that include a biologic such as a monoclonal antibody. While the industry has been successful in its efforts to lower the viscosity of many aqueous composition containing biologics, forming a composition suitable for injection, particularly intravitreal injection, can be particularly daunting. For an intravitreal injection in particular, it is typically desirable to use a very small gauge needle (i.e., typically at least 28 gauge and more typically at least 30 gauge) to avoid harm to the eye. However, pushing a viscous composition through such a small needle is particularly undesirable since it can be difficult for doctors to determine a proper amount of force to use to deliver the composition at a desired rate.
Intravitreal injections are particularly desirable for treating retinal diseases such as age related macular degeneration (AMD) since an injection device (e.g., a syringe with a needle) is typically used to located the injections in the vitreous closer to the retina, which is located at the back of the eye. Recently, it has been is discovered that an IgG1/lambda isotype monoclonal antibody is able to slow the advance of age related macular degeneration (AMD), see U.S. Patent Application No. 20100034809, which is incorporated herein by reference for all purposes. Unfortunately, the IgG1/lambda isotype monoclonal antibody, like many such antibodies, tends to significantly raise the viscosity of an aqueous compositions making it difficult to deliver as an intravitreal injection.
One mechanism for lowering the viscosity of an aqueous composition containing monoclonal antibodies is to include some amount of one or more selected chemical compounds capable of causing a viscosity reduction. Arginine, particularly L-arginine, has been found to be particularly effective in lowering the viscosity of aqueous compositions. However, it has been suggested that arginine, particularly L-arginine, can be toxic to the eye and other human tissue. See: Retinal Toxicity of Commercial Intravitreal Tissue Pasminogen Activator Solution in Cat Eyes, Charles J Hrach, MD; Mark W. Johnson, MD; Adam S. Hassan, MD; Bo Lei, MD; Paul A. Sieving, MD, Phd; Victor M. Elner MD, PhD, Arch Ophthalmol. 2000; 118:659-663; and Retinal Toxicity of Recombinant Tissue Pasminogen Activator in the Rabbit, Mark W. Johnson, MD; Karl R. Olsen, MD; Eleut Hernandez; W. David Irvine, MD; Robert N. Johnson, MD, Arch Ophthalmol. 1990; 108(2):259-263. Consequently, the pharmaceutical community, particularly the ophthalmic community, has avoided use of compounds such as arginine, particularly L-arginine, in ophthalmic compositions for lowering viscosity.
Unexpectedly, however, the inventors of the composition of the present invention have discovered that a group of compounds and particularly arginine can be used at relatively low concentrations to lower the viscosity of aqueous compositions containing particular biologics such as monoclonal antibodies, particularly IgG1/lambda isotype monoclonal antibodies. Further, it has been found that viscosity can be lowered enough to be suitable for injection and even suitable for intravitreal injection without harming the retina or other ocular tissue.